Slow release vehicles for minimizing skin irritancy of topical compositions

ABSTRACT

Staple, aqueous gel vehicles are provided for the topical application to the skin of irritating active ingredients such as retinoids, particularly tretinoin, with slow release of the active ingredient and minimal irritancy to the skin. The vehicles include a gelling agent effective to form a gel and hold the active ingredient in the aqueous medium for slow release on the skin, and an effective amount of an antioxidant to retard decomposition of the active ingredient. The vehicles and formulations are preferably aqueous emulsions which contain a solubilizing agent for the generally non-water soluble active ingredients, as well as usually an emulsifying agent and/or surfactant. Chelating agents, emollients, preservatives and other adjuvants and additives may also be included in the vehicles and formulations.

This application is the national share of PCT/US90/03219, filed Jun. 9,1990, U.S. Ser. No. 07/362529, filed Jun. 7, 1989 abandoned and Ser. No.07/429051, filed Oct. 30, 1989, abandoned.

FIELD OF THE INVENTION

The invention relates to stabilized, slow-release vehicles for normallyirritating, non-water soluble active ingredients for topical applicationto the skin. More particularly, the invention is directed to aqueousemulsion formulations of retinoids for topical application toindividuals who are sensitive to retinoids in other vehicles.

BACKGROUND OF THE INVENTION

Topical retinoids have been widely used for multiple cutaneousdisorders, as reported in A. Haas et al. "Selected TherapeuticApplications of Topical Tretinoin," JAAD, 15:870 (1986) (See Table Ibelow). In many instances, the application of tretinoin has alleviatedor induced remission in many such conditions, although these disordersreflect a variety of pathogenic mechanisms.

                  TABLE I                                                         ______________________________________                                        Selected Therapeutic Application                                              of Topical Tretinoin                                                          ______________________________________                                        Disorders with altered keratinization                                         Acneiform follicular, or nevoid                                               Nevus comdeonicus                                                             Senile comedones                                                              Steroid folliculitis                                                          Pseudofolliculitis                                                            Fox-Fordyce disease                                                           Hair casts                                                                    Monilethrix                                                                   Alopecia                                                                      Thrichiostasis spinulosa                                                      Linear verrucous nevus                                                        Ichthyosiform                                                                 Epidermolytic hyperkeratosis                                                  (congenital ichthyosiform                                                     erythroderma)                                                                 Ichthyosis vulgaris                                                           Lamellar ichthyosis                                                           X-linked ichthyosis                                                           Psoriasiform, hyperkeratotic, or                                              dyskeratotic                                                                  Acanthosis and pseudoachanthosis                                              nigricans                                                                     Callosites                                                                    Keratosis follicularis (Darier's)                                             Keratosis palmaris et plantaris                                               Kyrle's disease                                                               Psoriasis                                                                     Reactive perforating collagenosis                                             Infectious/inflammatory disorders                                             Molluscum contagiosum                                                         Flat warts                                                                    Plantar warts                                                                 Tinea versicolor                                                              Leg ulcers                                                                    Keloids and hypertrophic scars                                                Mucocutaneous disorders                                                       Geographic tongue                                                             Lichen planus                                                                 Leukoplakia                                                                   Xerophthalmia (dry eye)                                                       Hairy leukoplakia                                                             Pigmentation disorders                                                        Ephelides                                                                     Melasma                                                                       Postinflammatory hyperpigmentation                                            Malignant and premalignant disorders                                          Actinic keratoses, photoaging                                                 Keratoacanthomas                                                              Melanomas                                                                     Certival dysplasis                                                            Basal cell epithelioma                                                        ______________________________________                                    

It has been demonstrated that prolonged topical application of Vitamin Aacid (tretinoin or all-trans retinoic acid) is effective in thetreatment of acne (See U.S. Pat. No. 3,729,568 and Kligman, A. M.,"Topical Vitamin A Acid in Acne Vulgaris," Arch. Derm., 99: 469-476(1969)). Kligman utilizes a composition in which Vitamin A acid isdispersed in a water miscible (substantially oil- and fat-free) liquidcarrier having high solvating action. The topical application of thisVitamin A acid composition causes irritation of the skin in the treatedareas. A presently available gel form with alcohol base or creamformulation also causes irritation. (See U.S. Pat. Nos. 3,906,108 and4,247,547.)

A cream formulation of tretinoin is presently approved and iscommercially available from Ortho Pharmaceutical Company under thetrademark RETIN-A. It contains a therapeutically effective amount oftretinoin, a hydrophobic material selected from the liquid and solidfatty acids, fatty alcohols, fatty acid esters, pharmaceutical grades ofwaxes and hydrocarbons, the latter ranging from liquids throughsemisolids, such as petrolatum, to solids, and the like, a non-ionicemulsifier, xanthan gum, a preservative, an antioxidant and water. Thisformulation is more generally acceptable in a low dose 0.025%formulation, but it is still unacceptable to certain individuals withsensitive skin for continued daily applications.

Furthermore, the above tretinoin cream is relatively dense and pasty,and the pharmaceutical base is not elegant. The necessity to stabilizethe cream with xanthan gum and to apply daily or twice daily a fattysubstrate to the skin leaves a greasy film with a pasty residue.

Therefore, the problem has been to find vehicles for retinoids,particularly tretinoin, and other irritating active ingredients in whichthe active ingredient would remain stable and non-oxidized in thepresence of large amounts of water, while dramatically reducing theamount of irritation caused by the active ingredient. It is alsodesirable to have a vehicle which can provide sufficient hydration toallow good percutaneous absorption, while at the same time allowing theactive ingredient to be spread very thinly over the skin.

BRIEF SUMMARY OF THE INVENTION

According to the present invention, stable, aqueous retinoidformulations are provided for topical application to the skin, with slowrelease and stability of the retinoid and minimal irritancy to the skin.The formulations comprise an aqueous medium, an amount of retinoideffective for treatment of a skin condition, a gelling agent in anamount effective to form a gel and hold the retinoid in the aqueousmedium for slow release, and an antioxidant to retard decomposition ofthe retinoid in the aqueous medium. The formulations are particularlyadapted for use with tretinoin and dermatologically acceptable salts,isomers and derivatives thereof, and the gelling agent is preferably ahigh molecular weight polyacrylic acid which is neutralized to a pH ofabout 3 to 7.

In addition to the above ingredients, the formulations of the inventionpreferably also include a solubilizing agent for the retinoid, anon-ionic emulsifying agent to form a stable emulsion of the retinoid inthe aqueous medium, a lipophilic agent which may serve as an emollient,and a chelating agent to assist in holding the retinoid for slowrelease. Surfactants, preservatives and other suitable additives mayalso be included. Moreover, the aqueous emulsion vehicles according tothe present invention may also be used for the topical application ofother normally irritating, non-water soluble active ingredients besidesretinoids.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

According to the present invention, it has been found that vehiclesdescribed herein can be used very effectively in order to prevent andretard the amount of irritation caused by topically applied retinoids.These vehicles allow good percutaneous absorption and at the same timeprovide a very high degree of hydration without causing oxidation of theretinoid molecule. The use of a slow-release vehicle based on apolyacrylate gelling agent in an aqueous medium is surprising because ithas been thought previously that gels containing a high degree of waterwould cause great instability in the retinoid molecule. Also, it wasthought that a gel formulation containing water as a primary base wouldlead to residues of retinoid aggregating on the skin without allowingpercutaneous absorption, thereby leading to an inactive retinoid productwhich would readily oxidize on the skin.

I have discovered that surprisingly the gelling agent actually acts as acompound which allows stabilization of the retinoid and slowly releasesit so that it can optimally feed into the keratinocyte layers and dermalcells of the skin.

The vehicles and formulations of the present invention are particularlyuseful to patients who are sensitive to irritating active ingredients,particularly retinoids such as tretinoin. Thus, the slow-release vehicleprovides a great improvement in skin comfort and ease of application andreduces the side effects normally associated with topical application ofsuch active ingredients. The side effects, including erythema, stinging,peeling, crusting, and itching, may be sufficient to cause the patientto discontinue the application of the active ingredient before it can befully effective. Furthermore, the vehicles of the invention are morecosmetically acceptable and leave no residues of fatty or stickysubstances on the skin surface.

While the present invention is believed to be broadly applicable to avariety of normally irritating active ingredients for topicalapplication to the skin, and particularly to non-water soluble activeingredients, the invention has been found to be particularly useful forthe topical application of retinoids, particularly tretinoin, and thefollowing description will therefore be particularly directed tovehicles and formulations which have been designed for and tested withtretinoin. However, it will be understood that the broad teachings ofthis disclosure are applicable to other retinoids, and may be applicableto other normally irritating active ingredients for topical treatment ofthe skin.

As used in the present invention, the terms "aqueous" and "aqueousmedium" are intended to refer to vehicles and formulations in which themajor liquid component is water. Generally speaking, such vehicles andformulations will comprise at least 40% to 50% water and usually more.Thus, the vehicles and formulations of the present invention are to bedistinguished from formulations in which the major or primary liquid isan alcohol or other organic solvent.

The gelling agents useful in the present invention are those which forma gel in aqueous medium and hold the retinoid for slow release whileallowing the active ingredient to be spread over the skin in a thin,uniform layer while maintaining the integrity of the retinoid molecule.Particularly preferred gelling agents useful in the present inventionare the high molecular weight polyacrylate polymers (CAS 9003-01-4) andrelated polymers which are known agents for use in various types ofpharmaceutical and cosmetic compositions. These polyacrylates are formedby neutralizing polyacrylic acids with a base, such as sodium hydroxideor an amine, to an acid pH in the range of about 3 to 7. Theneutralization with a base causes the polyacrylic acid to swell(hydrate) to a gel.

Examples of commercially available polyacrylate gelling agents includethose sold under the trademark "CARBOPOL", available from the B. F.Goodrich Company. The CARBOPOL polymers have high molecular weightsranging from about 250,000 to about 4,000,000. The viscosity of thefinal gel is dependent on the polymer molecular weight, as well as theconcentration of the polymer in the vehicle or formulation. The gellingagent should be present in an amount of about 0.1 to 10 weight percent,depending upon the thickness of the gel desired.

Particularly preferred in the vehicles and formulations of the presentinvention is CARBOPOL 940 (pharmaceutical grade) which has molecularweights in the range of about 3,000,000 to 4,000,000. This gelling agentis preferably used in an amount of about 0.2 to 0.5 weight percent ofthe formulation or vehicle. Of course, it will be understood that otherCARBOPOL resins such as CARBOPOL 941, CARBOPOL 934P, etc., as well asother polyacrylates and other comparable gelling agents, may be used inthe vehicles and formulations of the present invention. In general, theuse of different molecular weight polyacrylates will only affect thedegree of viscosity obtained.

It has been found according to the invention that the polyacrylategelling agents have the surprising characteristic of retaining thereadily oxidizable retinoid compounds in a protected state, exposedoptimally only to the antioxidant. The gelling agent also efficientlyspreads the retinoid in a very fine layer over the stratum corneum,which allows percutaneous absorption without excessive spots of retinoidto cause skin reaction and irritation, which have been commonly seenwith the fatty substrates and gummy substances presently used asvehicles for retinoid application.

The active ingredients which are applied with the vehicles according tothe present invention are preferably retinoids which are commonly usedfor the treatment of various skin conditions, such as those describedabove. More particularly, the active ingredient is the commonly usedretinoid tretinoin (Vitamin A acid or all-trans retinoic acid), and itseffective, dermatologically acceptable salts, isomers and derivativesthereof, such as isotretinoin (13-cis-retinoic acid). However, asindicated above, other retinoids and other similarly irritating activeingredients may be used in the vehicles of the present invention to formdermatological compositions for topical treatment of the skin. Theretinoid will generally be present in the formulation in an amount ofabout 0.01 to 0.1 weight percent of the formulation, and preferablyabout 0.01 to 0.05 weight percent. However, the amount of retinoid orother irritating active ingredient may vary depending upon the strengthof the retinoid and the particular condition being treated.

Since the retinoid is more susceptible to oxidation and resultingdecomposition when present in an aqueous medium, the vehicles of thepresent invention must contain an antioxidant in proportion to theretinoid content. That is, the higher the concentration of the retinoid,the more antioxidant which will be required. Generally, the antioxidantshould be present in an amount of about 0.01 to 4 weight percent of theformulation. Suitable antioxidants include dl-alpha-tocopherol,butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), ascorbylpalmitate and propyl gallate, for example. Other suitable antioxidantsfor retinoids will be readily recognized by those skilled in the art.

In addition to the above ingredients, the vehicles and formulations ofthe present invention may optionally contain other agents and additiveswhich assist in the purposes of the present invention or which areconventionally used in topical dermatological compositions. Sinceretinoids are generally non-water soluble, it is generally preferred tofirst dissolve (solubilize) the retinoid in a solvent (solubilizingagent) for the retinoid. In the case of tretinoin, ethanol, isopropanolor another non-ionic alcohol in an amount of about 1 to 20 weightpercent of the formulation may be used to first solubilize the retinoid.Thereafter, the alcohol-solubilized retinoid may be combined with anemulsifier in order to form an emulsion in the aqueous medium. Theemulsifier is preferably at least one normally liquid glycol, preferablypropylene glycol, which may be present in the formulation in an amountof about 1 to 20 percent by weight.

When using a solubilizing agent and/or emulsifier, the formulations ofthe invention are preferably formed by first dissolving the retinoid inthe solubilizing agent and combining with the emulsifier and any otherorganic, lipophilic ingredients. In a separate vessel, the gelling agentis added to water and then neutralized to swell the gel. Thereafter, thesolubilized active ingredient and lipophilic agents are added to theswelled gel and mixed to form the final gel emulsion. It will berecognized, however, by those skilled in the art that other methods andmeans of emulsifying the active ingredient in the aqueous gel may beemployed consistent with the teachings of the present invention.

In order to assist the gelling agent in providing the slow release ofthe retinoid, the formulations of the invention may also include asuitable chelating or sequestering agent, preferably in an amount of upto about 0.5% by weight of the formulation. Suitable chelating agentsinclude, for example, sodium and calcium salts of EDTA, such as disodiumEDTA and calcium disodium EDTA.

Further, it may be desirable to include a surfactant as one of thecomponents of the vehicle. Thus, the inclusion of a surfactant may havethe dual benefit of helping to maintain the active ingredient in uniformsuspension in the formulation, while enhancing the bio-availability ofthe active ingredient. The surfactant may be present in an amount up toabout 20% by weight of the formulation, and may include for example,lecithin; sorbitan monoesters, such as sorbitan monoleate, sorbitanmonolaurate, sorbitan monopalmitate, sorbitan monostearate;polysorbates, such as those prepared from lauric, palmitic, stearic andoleic acids; polysorbate 20, mononylphenyl ethers of polyethyleneglycols, such as the monoxynols; polyoxyethylene monoesters, such aspolyoxeethylene monostearate, polyoxyethylene monolaurate,polyoxyethylene monoleate; dioctyl sodium sulfosuccinate; sodium laurylsulfate; and polyoximers having a molecular weight between 2,000 and8,000; triethanolamine; and ureas such as diazolidinyl urea. Preferably,a non-ionic surfactant is used if the stability of oxidizableingredients in the formulation is affected by the ionic strength of theformulation.

Further, the formulations may contain up to about 10 weight percent of alipophilic or hydrophobic agent, which may serve as an emollient oranti-irritant, as an additional help in relieving any irritation causedfrom the retinoid. Examples of such lipophilic agents include fattymaterials such as fatty alcohols of about 12 to 20 carbon atoms, fattyacid esters having about 12 to 20 carbon atoms in the fatty acid moiety,petrolatum, mineral oils, and plant oils such as soybean oil, sesameoil, almond oil, aloe vera gel, and allantoin.

The formulations and vehicles of the present invention may furthercontain about 0.05 to 2 weight percent of a preservative oranti-microbial or anti-bacterial agent which prevents bacterial ormicrobial growth in the gel. Preferred preservatives include theparabens, preferably methyl paraben and ethyl paraben, and sorbitol.However, other conventional preservatives commonly used inpharmaceutical compositions will be readily recognized by those skilledin the art.

Finally, the vehicles and formulations of the present invention mayoptionally contain minor amounts of such other commonly used cosmeticadjuvants or additives as dyes, perfumes, sunscreens, etc., as will bereadily recognized by those skilled in the art. In addition, it is alsocontemplated that the compositions of the invention may contain othertopical active medicaments such as vitamins, lipids, hormones oranti-inflammatory agents, such as corticosteroids.

The invention will now be illustrated in more detail with reference tothe following specific, non-limiting examples. The following formulationexamples were tested for their particular effectiveness in preventingthe oxidation of tretinoin. The formulations may contain varying amountsof tretinoin, such as 0.01, 0.025 or 0.05 weight percent. The results ofthese tests are set forth in Table II below, which shows the percentdecomposition of tretinoin in the formulation vehicle after 10 months.Additional decomposition results for formulatation Example 2 are setforth after Table II.

FORMULATION EXAMPLE NO. 1

    ______________________________________                                        Ingredient     Weight Percent                                                 ______________________________________                                        CARBOPOL 940                0.4                                               Ethanol                     3.0                                               Propylene glycol            3.0                                               BHT                         0.015                                             Parabens                    0.05                                              Tetrasodium EDTA            0.001                                             Polyethylene glycol 400     0.05                                              Triethanolamine             0.05                                              Water               q.s. to 100                                               All of the following Formulation Examples 2 through                           7 contain the following components in addition to                             those listed:                                                                 Parabens         0.05%                                                        Tetra-sodium EDTA                                                                               0.001%                                                      Polyethylene glycol 400                                                                        0.05%                                                        Triethanolamine  0.05%                                                        ______________________________________                                    

FORMULATION EXAMPLE NO. 2

    ______________________________________                                        Ingredient     Weight Percent                                                 ______________________________________                                        CARBOPOL 940                0.50                                              Propylene glycol            1.00                                              Ethanol                     2.00                                              BHT                         0.015                                             Water               q.s. to 100                                               ______________________________________                                    

FORMULATION EXAMPLE NO. 3

    ______________________________________                                        Ingredient     Weight Percent                                                 ______________________________________                                        CARBOPOL 940                 1.60                                             Propylene glycol             6.00                                             Ethanol                     10.00                                             BHT                          0.03                                             Water               q.s. to 100                                               ______________________________________                                    

FORMULATION EXAMPLE NO. 4

    ______________________________________                                        Ingredient     Weight Percent                                                 ______________________________________                                        CARBOPOL 940                 0.4                                              Propylene glycol            20.0                                              Ethanol                     20.0                                              BHT                          0.01                                             Water               q.s. to 100                                               ______________________________________                                    

FORMULATION EXAMPLE NO. 5

    ______________________________________                                        Ingredient     Weight Percent                                                 ______________________________________                                        CATBOPOL 940                 0.5                                              Propylene glycol            10.0                                              Ethanol                     20.0                                              BHT                          0.1                                              Water               q.s. to  100                                              ______________________________________                                    

FORMULATION EXAMPLE NO. 6

    ______________________________________                                        Ingredient     Weight Percent                                                 ______________________________________                                        CARBOPOL 940                 0.4                                              Propylene glycol             3.5                                              Isopropyl alcohol           10.0                                              BHT                          0.1                                              Water               q.s. to  100                                              ______________________________________                                    

FORMULATION EXAMPLE NO. 7

    ______________________________________                                        Ingredient     Weight Percent                                                 ______________________________________                                        CARBOPOL 940                0.3                                               Propylene glycol            1.20                                              Isopropyl alcohol           1.90                                              BHT                         0.01                                              Water               q.s. to  100                                              ______________________________________                                    

                  TABLE II                                                        ______________________________________                                        Stability Test Results                                                        Formulation  Percent Decomposition                                            Example No.  of Tretinoin (10 months)                                         ______________________________________                                        1            11                                                               2             5                                                               3             8                                                               4            11                                                               5             3                                                               7            13                                                               ______________________________________                                    

Formulation Example No. 2 was additionally tested for decomposition andfound to have 2% decomposition of tretinoin after one month and about13% decomposition of tretinoin after one year.

In order to test and demonstrate the effectiveness of the vehicles ofthe present invention in delivering retinoids in a less irritatingmanner while retaining therapeutic efficacy, the following studies wereperformed.

Animal Studies

In order to assess the bio-equivalency of tretinoin in an aqueous gelbase according to the present invention, compared to the presently FDAapproved formulation (RETIN-A), the Rhino mouse model was utilized.Thus, topical tretinoin produces a dose-dependent reduction in the sizeof the horn-filled utriculi in Rhino mouse epidermis. In this study,equivalent concentrations of tretinoin (0.025 weight percent) in theCARBOPOL gel formulation of Formulation Example No. 2 and in the RETIN-Acream vehicle were applied daily to the dorsal trunk skin of Rhino micefor up to two months. At two-week intervals, biopsies and photographswere taken to assess the effect of the tretinoin on histology, reductionof utriculi and general skin appearance. The resulting histology showedequivalent activity in the Rhino mouse epidermis treated with tretinoinin either the CARBOPOL gel formulation or the RETIN-A formulation.

Similar studies performed with Rhino mice skin at 0.05 percent andhigher concentrations of tretinoin showed equivalent activity in boththe CARBOPOL gel and RETIN-A formulations.

Clinical Studies

Seventy volunteer subjects participated in this study to assess thetherapeutic efficacy as well as the irritancy potential of aqueous gelformulations of the present invention versus the RETIN-A creamformulation. These subjects had all previously reported that they couldnot use the presently available formulations of tretinoin withoutexperiencing irritation sufficient to cause them to discontinue the useof the drug. Subjects were given either a 0.025% or 0.05% tretinoinformulation in the CARBOPOL gel formulation of Formulation Example No. 2above and were asked to apply the gel twice daily. These subjects werefollowed for six months, and results were evaluated by the attendingdermatologist as well as the patient.

Sixty-seven of the volunteers completed the study. As compared to the100% irritation reported by these volunteers who had all previously usedthe commercial 0.025% tretinoin formulation of RETIN-A, only 10 reportedirritation using the CARBOPOL gel formulation of Example 2 above. Ofthese, three reported mild irritation with the 0.025% gel formulation,six reported mild irritation with the 0.05% gel formulation, and onlyone reported moderate irritation with the 0.05% gel formulation. None ofthe subjects reported severe irritation with either concentration of thegel formulation.

These results demonstrate that the slow release CARBOPOL gelformulations of the present invention were less irritating than thestandard RETIN-A cream formulation. Subjects sensitive to RETIN-A wereable to tolerate equivalent and stronger concentrations of tretinoin inthe gel formulation without as much irritation, and therefore theycontinued to use the tretinoin as prescribed.

Additional subjects have been tested in studies with 0.01% tretinoin inthe gel formulations of the present invention, with similar resultsbeing obtained. In general, the slow release gel vehicles of the presentinvention appear to be an effective method of delivering tretinoin in aless irritating manner while still maintaining therapeutic efficacy.

The present invention may be embodied in other specific forms withoutdeparting from the spirit or essential attributes thereof and,accordingly, reference should be made to the appended claims, ratherthan to the foregoing specification as indicating the scope of theinvention.

I claim:
 1. A stable, aqueous retinoid composition for topicalapplication to the skin with slow release of the retinoid and minimalirritancy to the skin, comprising:(a) an aqueous medium such that thecomposition is at least about 40 weight percent water; (b) an amount ofretinoid effective for treatment of a skin condition; (c) an amount of ahigh molecular weight polyacrylic acid gelling agent neutralized to a pHof about 3 to 7 effective to form a gel and hold said retinoid for slowrelease in said aqueous medium; and (d) an amount of antioxidanteffective to retard decomposition of said retinoid in said aqueousmedium.
 2. A composition according to claim 1 comprising about 0.01 to0.1 weight percent retinoid, about 0.1 to 10 weight percent gellingagent, about 0.01 to 4 weight percent antioxidant, and at least about 50weight percent water.
 3. A composition according to claim 1 wherein saidretinoid is selected from the group consisting of tretinoin andeffective, dermatologically acceptable salts, isomers and derivativesthereof.
 4. A composition according to claim 1 wherein said antioxidantis selected from the group consisting of dl-alpha-tocopherol, butylatedhydroxyanisole, butylated hydroxytoluene, ascorbyl palmitate, and propylgallate.
 5. A composition according to claim 1 which includes about 0.1to 20 weight percent of a solubilizing agent for said retinoid.
 6. Acomposition according to claim 5 wherein said solubilizing agent isethanol.
 7. A composition according to claim 1 which includes about 0.1to 20 weight percent of a non-ionic emulsifying agent to form a stableemulsion of said retinoid in water.
 8. A composition according to claim7 wherein said emulsifying agent comprises at least one normally liquidglycol.
 9. A composition according to claim 1 which contains asurfactant selected from the group consisting of lecithin, sorbitanmonoesters, polysorbates, mononylphenyl ethers of polyethyleneglycols,polyoxyethylene monoesters, dioctyl sodium sulfosuccinate, sodium laurylsulfate, polyoxamers having a molecular weight of 2000 to 8000,triethanolamine, and ureas.
 10. A composition according to claim 1 whichincludes up to about 10 weight percent of a lipophilic agent.
 11. Acomposition according to claim 10 wherein said lipophilic agent isselected from the group consisting of fatty alcohols of about 12 to 20carbon atoms, fatty acid esters having about 12 to 20 carbon atoms inthe fatty acid moiety, petrolatum, plant oils and mineral oils.
 12. Acomposition according to claim 1 which contains about 0.05 to 2 weightpercent of a preservative.
 13. A composition according to claim 12wherein said preservative is selected from the group consisting ofmethyl paraben, ethyl paraben and sorbitol.
 14. A composition accordingto claim 1 which includes up to about 0.5 weight percent of a chelatingagent for said retinoid.
 15. A composition according to claim 14 whereinsaid chelating agent is selected from the group consisting of sodium andcalcium salts of EDTA.